Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension

Am J Respir Crit Care Med. 2019 Apr 1;199(7):891-902. doi: 10.1164/rccm.201807-1236OC.

Abstract

Rationale: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH.

Objectives: To determine how an acquired deficiency of BMP9 signaling might contribute to PAH.

Methods: Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH.

Measurements and main results: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone.

Conclusions: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

Keywords: bone morphogenetic protein; portal hypertension; portopulmonary hypertension; pulmonary arterial hypertension; signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Bone Morphogenetic Proteins / metabolism*
  • Female
  • Humans
  • Hypertension, Portal / metabolism*
  • Hypertension, Portal / physiopathology*
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / physiopathology*
  • Liver Diseases / metabolism*
  • Liver Diseases / physiopathology*
  • Male
  • Middle Aged

Substances

  • Biomarkers
  • Bone Morphogenetic Proteins